Intravascular levels of
low-density lipoprotein cholesterol (
LDL-C) at approximately ≤ 0.6 mmol/L are likely to minimize, and perhaps eliminate,
LDL-C-related vascular toxicity while having no effect on essential, intracellular
cholesterol homeostatic pathways, according to accumulated knowledge from basic science. Randomized clinical trials, observational reports, and Mendelian randomization trials are also forcing a reconsideration of what "normal"
LDL-C means. Recent trials of
secondary prevention have substantiated that such levels are safe and associated with a decreased risk of cardiovascular events (CVEs) compared with patients with higher levels of
LDL-C. Similarly, treatment to this low range is associated with regression and stabilization of established
atherosclerosis. Primary prevention trials also show that low levels of
LDL-C are safe and associated with decreased risk of CVEs through
cholesterol-lowering in adults with
LDL-C ≥ 3.5 mmol/L or when levels are < 3.5 mmol/L in association with other cardiovascular risks. Although there are no randomized clinical outcome trials of
familial hypercholesterolemia patients, such patients have very high, lifetime risk of CVE, and registry studies show that
LDL-C reduction has nearly normalized their CVE rates. The possibility of
familial hypercholesterolemia should be considered if
LDL-C is > 4.5 and > 4.0 mmol/L at ages 18-39 years and younger than 18 years, respectively. On the basis of these convergent and internally consistent lines of evidence, in this article we speculate on a translational paradigm aimed at eliminating
LDL-C-related CVEs through aggressive primary prevention strategies that are already proven and well accepted in principle.